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Umpolung Synthesis

-see Furhop, J.-H.; Li, G. Organic Synthesis-Concepts and Methods, Wiley-VCH, 2003.

Organic molecules have innate reactivity patterns imposed upon them by virtue of the functional groups

within their structures. This was taken advantage of extensively in the 331 course; for example:

R R

O

δδδδ+

due to the electronegativity differencebetween O and C

and

RR'

O

δδδδ-

due tobase

RR'

O

_ RR'

O_

In fact, this pattern of alternating reactivity can continue infinitely as long as the conjugated multiple

bonds continue, as in

As a result, certain functional group patterns are easy to make, such as 1,3-dioxygenated compounds, or

1,5-dioxygenated compounds. The same could be said for nitrogen containing compounds, but we will

focus on the former.

RR1

O

_+

R2 H

O

R R2

OHO

R1

can manipulate oxidation statesby oxidation/reduction reactions

1,3-dioxygenated cpds

1,5-dixogenated cpds

RR1

O

_

R2

O

+R R2

O O

R1R

R1

OR2

O

_

+12

3

45

21

3

So, the question then becomes, how does one go about making 1,2-dioxygenated and 1,4-dioxygenated

compounds?

What is required is some way of inverting reactivity of carbonyl or carbonyl-like compounds. This

‘inverted’ reactivity is called Umpolung reactivity (or Umpolung synthesis).

R

O

δδδδ+ δδδδ+δδδδ+ δδδδ+δδδδ-

δδδδ- δδδδ- δδδδ-δδδδ-Umpolung reactivity

R

O

δδδδ+

δδδδ+δδδδ+δδδδ+ δδδδ+

δδδδ- δδδδ- δδδδ- δδδδ-

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-For a text, see Umpoled Synthons, Hase, T. A., Ed.; Wiley Interscience, 1987.

Let’s start with 1,2-dioxygenated compounds

1,2-Dioxygenated compounds

Reasoning from first principles, making these compounds with require one of two approaches, either:

R

O_

acyl anion

+H R1

O

RR1

O

OH

" "

or

RR1

O

_RR1

O_

+ " +O-R2 " RR1

O

OR2electrophilicoxygen

A. We’ll start with the 1st approach. What can we possibly do for an acyl anion equivalent?

(see Wyatt, Warren, Ch. 14; Furhop, Ch. 1.7)

1) Acetylide anions. Recall that terminal alkynes are relatively acidic, especially for hydrocarbons. This

can be used; so…

H

H

pK a = 25

MeLi

THF or Et 2O H

Li≡≡≡≡

CC

H

_

H

Li + R H

O

not normally isolated but stableat low temperature

orR R1

O

1) add

2) H2O workupR

OH

H

R

OH

HR1or

This can be convertable into a 1,2-dioxygenated compound, by an electrophilic addition of water across

the triple bond. Recall that this requires an Hg2+ salt to make this happen.

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H

R

OHHg2+

H+, H2O

R

OH

H

H

+

R

OH

+H

H

R

OH

OH

H

H

R

OH

H3C

O

favoured

disfavoured

This is somewhat limited, because it is only applicable to the anion of acetylene (ethyne) itself. If there

are more substituents on the alkyne, there is a problem with the regiochemistry of H2o addition to the

propargyl alcohol. On the other hand, since acetylene/acetylide is small, this transformation often works

with sterically hindered carbonyl partners.

R1

R

OHHg2+

H+, H2OR

OH

R1

H

+or

R

OHR1

H

+

neither strongly preferred-get mixture of H 2O addition

products

Other Sources of X- ̅CH2

Cyanide ion C̅N commercially available as NaCN, KCN, from H-CΞN pKa = 9.2

Nitroalkanes

Dithianes

S S

R H

base

pK a = 36.5 - 39pK a LDA = 41-44 (DMSO), 35.7 (H2O)

S S

R_

anion stabilized by-polarizability of weaker C-S bond-overlap with σσσσ* of C-S (negative hyperconjugation)

2. Cyanide Ion

Cyanide ion will add to most aldehydes and ketones reversibly to give a cyanohydrin. It is more often

base catalyzed, but acid and Lewis acid catalyzed versions are known as well.

H3CNO2

base

pK a = 10 (H2O)17.2 (DMSO - Bordwell pK a)

H2CN

O

O

H2CN

O

O_ _

_

_

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R R1

O+ HCN

R R1

OH +

+CN

R CN

OH

R1

R R1

O+ H-C≡≡≡≡N + base base-H + + CN +

R R1

O

base-H + + R CN

O

R1

_

R CN

OH

R1+ base

This sometimes has problems with forcing the reaction to the product side, and a competing benzoin

condensation, so the reaction is usually performed by trimethylsilyl cyanide and a Lewis acid.

Me3Si C≡≡≡≡N + R R1

OBF3-OEt2

CH2Cl2R CN

O-SiMe3

R1 R CN

OH

R1

Hydrolysis of the nitrile function can now give the α-hydroxy acid. Acidic conditions are usually used

because of the competing cyanohydrin reversal under basic conditions.

For some related chemistry, see the Strecker amino acid synthesis, and the benzoin condensation.

R R1

O+ NaCN + NH4Cl

R CN

NH2

R1

Streckersynthesis

Ar H

O+ KCN Ar

OH

Ar

O

2Benzoincondensation

Note: The benzoin condensation is becoming increasingly im portant

The benzoin condensation is becoming increasingly important, so it is worth some elaboration. The

original version is cyanide ion catalyzed, and involves yet another acyl anion equivalent in the process.

The reaction is most often accomplished on aldehydes without acidic α- protons, to avoid aldol type

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reactions competing; there are exceptions. In addition, it is normally a dimerization of two identical

aromatic aldehydes or an intramolecular reaction, so that ‘crossed’ Benzoin regiochemistry issues are

avoided. Finally, practically, cyanide sources largely have been replaced by things like thiazolium ions.

Note that the deprotonated thiazolium may be considered as an N-heterocyclic carbene (NHC); it is the

NHC that would serve in an analogous manner to cyanide ion.

Ar H

O

+ -CN Ar H

O

NC

_

Ar CN

OH_ +

Ar H

O

Ar

OH

Ar

NCO

H

_

Ar

O

Ar

NCOH

H

_

ArAr

OH

O

+ -CN

S

NH

+ base

thiazoliumion

S

N+_

S

N:

carbene

3. Dithianes

See Clayden p 1254 (1st ed), p. 660 (2nd ed)

Dithianes are for most purposes simply the sulphur version of acetals. They are made quite similarly,

usually using a ketone or aldehyde, a Lewis acid (instead of a protic one), 1,3-propanedithiol, and an

appropriate solvent.

R R1

O

SH SH+

BF3-OEt2

CH2Cl2, rt S S

R R1

These will function as protecting group in for many of the same transformations as conventional acetals,

but if one of R or R1 is an H, a strong base (such a n-BuLi) will abstract that proton. The resultant anion is

highly nucleophilic, and will attack aldehydes and many ketones.

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S S

H3C H

1) n-BuLi, THF, -20 o

2)CHO

-78 o to RT

S S

H3C

LiO

3) H2OS S

H3C

HO

There are several methods of ‘hydrolysis ‘ of dithianes; since S is a ‘soft’ base, a proton has much less

affinity for S thanfor O. As a result, Hg2+, a soft Lewis acid, is excellent where S is concerned.

S S

H3C

HO

Hg(ClO4)2, MeOH

CH2Cl2, RT

(or HgCl 2, H2O)

O

H3C

OH

See Comprehensive Organic Synthesis, VI, p. 677; Yus, M. Tetrahedron 2003, 59, 6147.

For other deprotection conditions, see Wuts, P. G. M. Protective Groups in Organic

Synthesis (2nd, 4th Ed –my office; 3rd Ed-Dr. Eichhorn)

There is an issue sometimes, that the dithiane anions are more susceptible to steric hindrance than

acetylide ions.

O

S S

H3C Li H Na

1) NH3 (l), -35 o

2) H2O OH

H

OH

SS

Note: There are other version of dithianes which are partially oxidized ones, i.e.,

4. And what about nitro compounds?

It is possible to get aldol type reactions with nitro compounds and aldehydes or ketones; it is well known

as the Henry reaction.

-in fact, the nitro group is so electron withdrawing that a dianion nitroalkanes can be made

The problem with the Henry reaction approach, though, is that the ‘hydrolysis’ of the nitro function to a

carbonyl is not successful for these types of compounds. Elimination reactions and ‘retro’-Henry

S S

H3C H

O

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reactions compete. On the other hand, there are other transformations of a nitro compound that do

work to give other types of 1,2-difunctionalized compounds.

N

NP

N

N

i-Pr i-Pr

Pr-i

10 mol%

MgSO4 (2.2 equiv)

NO2

R-CHO

NO2

OHR

PCC

NH

+

ClCrO 3-

R

NO2

O

H2,5% Pd-C

R

NH2

OH

Kisanga, P. B.; Verkade, J. G.*J. Org. Chem. 1999, 64, 4298.

For reviews on the Henry reaction, see; Rosini, G. Comprehensive Organic Synthesis, II, Ch. 1.10 (p. 321)

Rosini, G.; Ballini, R. Synthesis, 1988, 833.

Luzzio, F. A. Tetrahedron, 2001, 57, 915.

An example of its use in synthesis….

H

O

O O

1) H3C-NO2,NaOEt

2) H+ OO2N

HOH2

Pd-C NH

HO

Brown, E. Tetrahedr on 1973, 29, 455.

B. Oxygen Electrophiles for Enolates

The alternative approach to doing an aldol- type reaction on an acyl anion equivalent, is to react a fairly

conventional enolate with some O+ equivalent. This is obviously very difficult due to the electronegative

nature of oxygen, and the representation below is the six valent electron, O+ species that you’ve been

told is not accessible.

R

O_

R

O_ + O+-R1

R

O

OR1

In truth, it’s really not quite as bad as that, since many reactions of enolates are SN2, and so we don’t

really need a truly cationic oxygen. What we really need is for …….

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R

O_ +

R1 OX R

OO

R1

X

δδδδ-

δδδδ-

R

O

OR1 + X-

to be better than….

R

O_ +

OX R

OX

OR1

δδδδ-

δδδδ-

R

O

X + R1-O-

R1

As a result, there is a reasonable chance at being successful with reagents such as..

R1 OO

R2 or R1 ON

EWG

EWGX X

especially using the relief of ring strain to help the reaction.

There are two particularly well known manifestations of this.

1) The Vedejs reagent, known of MoOPh, which is MoO5-pyr-HMPA.

It’s prepared by oxidation of MoO3…

MoO3 + H2O2 + HMPA + pyridine

Mo

O

N OO

OO

O

P

Me2N NMe2NMe2

"MoOPh"

Org. Synth. 1985, 64, 127.

It reacts with enolates by attack on one of the oxygen atoms, with opening of the 3 membered ring.

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Mo

O

N OO

OO

O

P

Me2N NMe2NMe2

O

_

Mo

O

pyr HMPAO-

OO

O

O

Na2SO3(aq)O

OH

An actual example..

D-(+)-camphor

1) LDA, THF, -78 o

2) MoOPh, -20 o

3) Na2SO3(aq)

77%

O+

O

trace

OOH

H

O

Advantages - This works well with enolates derived from.. Ketones, esters (or lactones), amides, nitriles.

Disadvantages – i) One can get some α-diketone as side- product

ii) It works poorly with unhindered (i.e., methyl derived) enolates

iii) HMPA is a carcinogen – on the other hand, the DMPU adduct (known as MoOPD) is

known, and it seems to work reasonably well (Anderson, J. D.; Smith, S. C. Synlett 1990, 107)

N N

O

1,3-Dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone= DMPU

2) The Davis Oxaziridines

If you substitute a 3 membered ring with an oxygen and a nitrogen (oxaziridine) with a strong

electron withdrawing group on N, the N- is actually the better leaving group…

O

NAr

SAr

OO

strong electronwithdrawing group

oxaziridine

pK a's ArS

O

NH

O

R

pK a 17 (DMSO)?? (H2O)

R

OH

ArpK a 29-30 (DMSO)

17 (H2O)

See Davis, F. A.; Shepperd, A. C. Tetrahedron 1989, 45, 5703 (general)

Davis, F. A.; Chen, B.-C. Chem. Rev. 1992, 92, 919. (asymmetric)

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So if an enolate is reacted with an N-sulfonyl oxaziridine…

O

NPh

SPh

OO

R

O-M+

R1

R

O

R1

_

R

O

R1

O

Ph

NSO2Ph

_

hemi N,O-acetal (ate)

R

O

R1

O

Ph

N

SO2Ph_+

H2O

R

O

R1

OH

αααα-hydroxy carbonylThere is one drawback - if the breakdown of the N,O-acetal ate intermediate is too fast relative to the

attack of the enolate on the oxaziridine, you’ll get a competing amount of …

R

O

R1

Ph

N

H

SO2Ph

This is the major side product for oxygenation of ketone and ester enolates. It is substantial with lithium

enolates, but much less significant with sodium or (especially) potassium enolates. For amide enolates,

which tend to be more reactive, the lithium enolates are normally fine. So….

O1) KHMDS

2) PhSO2N(O)CHPh

3) H2O

O

OH

85%

yields often better than with MoOPh

KHMDS = NSiMe3

SiMe3

K+_

Aside: There is also an excellent method for α- hydroxyl incorporation using silyl enol ethers, involving

an epoxidation. It is sometimes called the Rubottom oxidation. (COS VII, p. 163)

R

OSiMe3

R1

m-CPBA

R

Me3SiO

R1

O OO

Me3Si

RR1

+

_

R

O

R1

OHR

O

R1

OSiMe3H2O